Aspirin (acetylsalicylic acid), one of the oldest over-the-counter drugs having been marketed since 1899, continues to be used for relief from headaches, fevers and arthritis pain. Aspirin works as an analgesic to reduce pain, an anti-pyretic to reduce fever and an anti-inflammatory agent. Recently, aspirin has been shown to aid in the prevention of heart attacks. However, aspirin does have undesirable side effects. Use of aspirin has been linked to Reye's Syndrome in children, hearing impairment in heavy users, stomach problems, excessive bleeding and certain rare but serious complications of pregnancy.
Other anti-inflammatory drugs that reduce pain such as acetaminophen (under the trade name Tylenol) and ibuprofen (under the trade names Motrin, Advil and Nuprin) are also available. However, these also are associated with potentially harmful side effects. Acetaminophen, the most preferred analgesic after aspirin, can cause delayed liver damage when used excessively and major kidney damage with long-term chronic use. Accordingly, there is still a need for analgesic, anti-pyretic and anti-inflammatory drugs that can be used in place of aspirin, ibuprofen and acetaminophen.
A listing of human cancers for which chemotherapy has exerted a predominant role in increasing life span, approaching normal life expectancy, includes Burkitt's lymphoma, acute lymphocytic leukemia and Hodgkin's disease, along with about 10–15 other tumor types. See, for example, Golden et al., Eur. J. Cancer, 12, 129 (1981) (Table 1). While the cure rate of these cancers illustrates the level of success of screening systems in selecting antitumor agents that are effective in man, these responsive tumors represent only a small fraction of the various types of cancer and, notably, there are relatively few drugs highly active against clinical solid tumors. Such drugs include cyclophosphamide, adriamycin, 5-FU, hexamethylmelamine and the like. Thus, patients with many types of malignancies remain at significant risk for relapse and mortality.
After relapse, some patients can be reinduced into remission with their initial treatment regimen. However, higher doses of the initial chemotherapeutic agent or the use of additional agents are frequently required, indicating the development of at least partial drug resistance. Recent evidence indicates drug resistance can develop simultaneously to several agents, including ones to which the patient was not exposed. The development of multiple-drug resistant (MDR) tumors may be a function of tumor mass and constitutes a major cause of treatment failure. To overcome this drug resistance, high-dose chemotherapy with or without radiation and allogenic or autologous bone marrow transplantation can be employed. The high-dose chemotherapy may employ the original drug(s) or be altered to include additional agents. The development of new drugs non-cross resistant with MDR phenotypes is required to further the curative potential of current regimens and to facilitate curative interventions in previously treated patients.
Recently, the in vitro anti-tumor activity of a novel class of natural products called illudins has been examined. See Kelner et al., Cancer Res., 47, 3186 (1987). The extreme toxicity of illudins has prevented any applications in human tumor therapy. Recently, synthetic analogs of the illudins have been developed which exhibit promising antitumor activity. See, for example, U.S. Pat. No. 5,439,936 (Kelner et al), issued Aug. 8, 1995 and U.S. Pat. No. 5,523,490 (Kelner et al), issued Jun. 4, 1996. These include hydroxymethylacylfluvene (HMAF) which has recently shown promise as an antitumor drug. See Zurer, Chem. Eng. News, page 7 (Feb. 10, 1997). See also U.S. Pat. No. 6,025,328 (McMorris et al), issued Feb. 15, 2000 and U.S. Pat. No. 6,069,283 (McMorris et al), issued May 30, 2000, which disclose various illudin analogs, including HMAF analogs having glucose, fructose, sucrose, ribose, deoxy sugar, e.g., deoxyribose, substituents (see Compound 18 in column 12 from Example I of U.S. Pat. No. 6,069,283) useful as antitumor agents (see Example III of U.S. Pat. No. 6,069,283 where Compound 18 is tested for antitumor activity). However, there still exists a continuing need for chemotherapeutic agents which inhibit tumor growth, especially solid tumor growth, and which have an adequate therapeutic index to be effective for in vivo treatment. In particular, U.S. Pat. No. 6,025,328 (see column 6, lines 43–60) says that its illudin analogs can be in racemic, optically active and steroisomeric forms. These various forms of illudin analogs would be expected to have significantly different biological activity, making it difficult to predict which illudin analogs would be expected to have the desired therapeutic activity for effective treatment.